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Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats

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Abstract

Rationale and objectives

The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 melatonin receptor agonist/5-HT2c serotonin receptor antagonist.

Results

Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3- or 6-week treatment with agomelatine (40–50 mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a “disease-dependent” drug.

Conclusions

These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders.

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Acknowledgements

This study was supported by the University of Lille North 1 and the Sapienza University of Rome (Frame Agreement signed between the two universities on 15/02/2007) and by CNRS in the framework of the European Research Team (GDRE 691) “Early Programming of Modern Diseases”.

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Authors and Affiliations

  1. Neuroplasticity Team, UMR 8576 CNRS Structural and Functional Glycobiology Unit, University Lille North of France (USTL), 59655, Villeneuve d’Ascq, France

    Sara Morley-Fletcher, Jerome Mairesse, Ferdinando Nicoletti & Stefania Maccari

  2. IC2N, IBDLM, UMR6216, CNRS, Marseille, France

    Amelie Soumier, Mounira Banasr & Annie Daszuta

  3. Azienda Sanitaria Locale, RM.E. Unità Operativa Complessa Adolescent, Rome, Italy

    Francesca Fagioli

  4. Institut de Recherches Internationales Servier, Courbevoie, France

    Cecilia Gabriel & Elisabeth Mocaer

  5. Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, USA

    Bruce McEwen

  6. Department of Human Physiology and Pharmacology, Sapienza University, Rome, Italy

    Ferdinando Nicoletti

  7. I.N.M. Neuromed, Pozzilli, Italy

    Ferdinando Nicoletti

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  1. Sara Morley-Fletcher
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  2. Jerome Mairesse
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  3. Amelie Soumier
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  6. Cecilia Gabriel
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  8. Annie Daszuta
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  9. Bruce McEwen
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  10. Ferdinando Nicoletti
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  11. Stefania Maccari
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Correspondence to Stefania Maccari.

Additional information

S. Morley-Fletcher and J. Mairesse contributed equally to this work.

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Morley-Fletcher, S., Mairesse, J., Soumier, A. et al. Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacology 217, 301–313 (2011). https://doi.org/10.1007/s00213-011-2280-x

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